Selected 2017 Publications

'Rinse and Replace': Boosting T Cell Turnover To Reduce HIV-1 Reservoirs.

Grossman Z, Singh NJ, Simonetti FR, Lederman MM, Douek DC, Deeks SG, .

Trends Immunol. 2020 May;():. doi: 10.1016/j.it.2020.04.003. Epub.

Abstract: Latent HIV-1 persists indefinitely during antiretroviral therapy (ART) as an integrated silent genome in long-lived memory CD4 T cells. In untreated infections, immune activation increases the turnover of intrinsically long-lived provirus-containing CD4 T cells. Those are 'washed out' as a result of their activation, which when coupled to viral protein expression can facilitate local inflammation and recruitment of uninfected cells to activation sites, causing latently infected cells to compete for survival. De novo infection can counter this washout. During ART, inflammation and CD4 T cell activation wane, resulting in reduced cell turnover and a persistent reservoir. We propose accelerating reservoir washout during ART by triggering sequential waves of polyclonal CD4 T cell activation while simultaneously enhancing virus protein expression. Reservoir reduction as an adjunct to other therapies might achieve lifelong viral control. © Trends In Immunology.

"Inflammescent" CX3CR1+CD57+ CD8 T cells are generated and expanded by IL-15.

Morris SR, Chen B, Mudd JC, Panigrahi S, Shive CL, Sieg SF, Cameron CM, Zidar DA, Funderburg NT, Younes SA, Rodriguez B, Gianella S, Lederman MM, Freeman ML.

JCI Insight 2020 May;():. doi: 10.1172/jci.insight.132963. Epub.

Abstract: HIV infection is associated with an increase in the proportion of activated CD8 memory T cells (Tmem) that express CX3CR1, but how these cells are generated and maintained in vivo is unclear. We demonstrate that increased CX3CR1 expression on CD8 Tmem in people living with HIV (PLWH) is dependent on coinfection with human cytomegalovirus (CMV), and CX3CR1+ CD8 Tmem are enriched for a putatively immunosenescent CD57+CD28- phenotype. The cytokine IL-15 promotes the phenotype, survival, and proliferation of CX3CR1+CD57+ CD8 Tmem in vitro, whereas TCR stimulation leads to their death. IL-15-driven survival is dependent on STAT5 and Bcl-2 activity, and IL-15-induced proliferation requires STAT5 and mTORC1. Thus, we identify mechanistic pathways that could explain how "inflammescent" CX3CR1+CD57+ CD8 Tmem dominate the overall memory T cell pool in CMV-seropositive PLWH and that support reevaluation of immune senescence as a nonproliferative dead-end. © JCI Insight.

Presence of asymptomatic cytomegalovirus and Epstein--Barr virus DNA in blood of persons with HIV starting antiretroviral therapy is associated with non-AIDS clinical events.

Gianella S, Moser C, Vitomirov A, McKhann A, Layman L, Scott B, Caballero G, Lada S, Bosch RJ, Hoenigl M, Lurain N, Landay A, Lederman MM, Hunt PW, Smith D.

AIDS 2020 May;34(6):849-857. doi: 00002030-202005010-00005. Epub.

Abstract: Even with antiretroviral therapy (ART), persons with HIV (PWH) experience increased morbidity and mortality. Cytomegalovirus (CMV) and Epstein--Barr virus (EBV) co-infections likely exacerbate inflammatory-related diseases. © AIDS (London, England).

Cytomegalovirus Coinfection Is Associated with Increased Vascular-Homing CD57 CD4 T Cells in HIV Infection.

Chen B, Morris SR, Panigrahi S, Michaelson GM, Wyrick JM, Komissarov AA, Potashnikova D, Lebedeva A, Younes SA, Harth K, Kashyap VS, Vasilieva E, Margolis L, Zidar DA, Sieg SF, Shive CL, Funderburg NT, Gianella S, Lederman MM, Freeman ML.

J. Immunol. 2020 May;204(10):2722-2733. doi: 10.4049/jimmunol.1900734. Epub.

Abstract: Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both HIV and CMV infections, both of which are associated with increased risk of cardiovascular disease (CVD). In this study, we identify CMV coinfection as a major driver of the cytotoxic phenotype, characterized by elevated CD57 expression and reduced CD28 expression, in circulating CD4 T cells from people living with HIV infection, and investigate potential mechanisms linking this cell population to CVD. We find that human CD57 CD4 T cells express high levels of the costimulatory receptor CD2 and that CD2/LFA-3 costimulation results in a more robust and polyfunctional effector response to TCR signals, compared with CD28-mediated costimulation. CD57 CD4 T cells also express the vascular endothelium-homing receptor CX3CR1 and migrate toward CX3CL1-expressing endothelial cells in vitro. IL-15 promotes the cytotoxic phenotype, elevates CX3CR1 expression, and enhances the trafficking of CD57 CD4 T cells to endothelium and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of activated CD57 CD4 T cells and expression of CX3CL1 and LFA-3 in atherosclerotic plaque tissues from HIV-uninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to CVD in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2/LFA-3-mediated costimulation. This study identifies several targets for therapeutic interventions and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in people living with HIV infection. © Journal Of Immunology (Baltimore, Md. : 1950).

Compulsory Immunization Protects Against Infection: What Law and Society Can Do.

Mehlman MJ, Lederman MM.

Pathog Immun 2020 ;5(1):1-7. doi: pai.v5i1.344. Epub.

Abstract: Since their broad implementation, immunizations have decreased morbidity and mortality due to a number of serious infectious diseases. In recent years, exaggerated concerns about the safety of immunizations have resulted in decreased immunization coverage in many regions and epidemic outbreaks of serious transmissible diseases - most particularly measles. This commentary reviews the legal justification for compulsory immunization and the ethical justification for civil incentives to assure compliance with immunization practices. © Pathogens & Immunity.

Association of Lymphopenia With Risk of Mortality Among Adults in the US General Population.

Zidar DA, Al-Kindi SG, Liu Y, Krieger NI, Perzynski AT, Osnard M, Nmai C, Anthony DD, Lederman MM, Freeman ML, Bonomo RA, Simon DI, Dalton JE.

JAMA Netw Open 2019 Dec;2(12):e1916526. doi: 10.1001/jamanetworkopen.2019.16526. Epub.

Abstract: Immune dysregulation can increase the risk of infection, malignant neoplasms, and cardiovascular disease, but improved methods are needed to identify and quantify immunologic hazard in the general population. © JAMA Network Open.

Highly oxidized low-density lipoprotein mediates activation of monocytes but does not confer interleukin-1β secretion nor interleukin-15 transpresentation function.

Sieg SF, Bazdar DA, Zidar D, Freeman M, Lederman MM, Funderburg NT.

Immunology 2020 02;159(2):221-230. doi: PMC6954695. Epub.

Abstract: Oxidized low-density lipoprotein (LDL) contributes to cardiovascular disease in part by mediating activation and maturation of monocytes and macrophages. Furthermore, co-localization studies using histochemical approaches have implicated a potential role for oxidized LDL as a mediator of interleukin-15 (IL-15) expression in myeloid cells of atherosclerotic plaque. The latter activity could be an important pro-inflammatory mechanism that mediates myeloid cell/T-cell crosstalk. Here, we examined the responses of primary human monocytes to highly oxidized LDL molecules. Oxidized LDL readily induced secretion of chemokines MCP-1 (CCL2) and GRO-α (CXCL1) but unlike lipopolysaccharide (LPS), has limited capacity to induce a variety of other cytokines including tumor necrosis factor-α, IL-6, IL-1β and interferon-γ-induced protein-10 and also displayed a poor capacity to induce p-Akt or P-S6 signaling. Failure of oxidized LDL to induce IL-1β secretion was associated with limited induction of caspase-1 activation. Furthermore, despite finding evidence that oxidized LDL could enhance the expression of IL-15 and IL-15 receptor expression in monocytes, we found no evidence that it could confer IL-15 transpresentation capability to these cells. This observation contrasted with induction of IL-15 transpresentation in lipopolysaccharide-stimulated monocytes. Overall, our data suggest that highly oxidized LDL is a selective inducer of monocyte activation. Sterile inflammatory mediators, particularly those implicated in Toll-like receptor 4 signaling, may play a role in vascular pathology but the activities of these agents are not uniform. © Immunology.

Fingolimod retains cytolytic T cells and limits T follicular helper cell infection in lymphoid sites of SIV persistence.

Pino M, Paganini S, Deleage C, Padhan K, Harper JL, King CT, Micci L, Cervasi B, Mudd JC, Gill KP, Jean SM, Easley K, Silvestri G, Estes JD, Petrovas C, Lederman MM, Paiardini M.

PLoS Pathog. 2019 10;15(10):e1008081. doi: PPATHOGENS-D-19-00870. Epub.

Abstract: Lymph nodes (LN) and their resident T follicular helper CD4+ T cells (Tfh) are a critical site for HIV replication and persistence. Therefore, optimizing antiviral activity in lymphoid tissues will be needed to reduce or eliminate the HIV reservoir. In this study, we retained effector immune cells in LN of cART-suppressed, SIV-infected rhesus macaques by treatment with the lysophospholipid sphingosine-1 phosphate receptor modulator FTY720 (fingolimod). FTY720 was remarkably effective in reducing circulating CD4+ and CD8+ T cells, including those with cytolytic potential, and in increasing the number of these T cells retained in LN, as determined directly in situ by histocytometry and immunohistochemistry. The FTY720-induced inhibition of T cell egress from LN resulted in a measurable decrease of SIV-DNA content in blood as well as in LN Tfh cells in most treated animals. In conclusion, FTY720 administration has the potential to limit viral persistence, including in the critical Tfh cellular reservoir. These findings provide rationale for strategies designed to retain antiviral T cells in lymphoid tissues to target HIV remission. © PLoS Pathogens.

Pneumoproteins are associated with pulmonary function in HIV-infected persons.

Jeon D, Chang EG, McGing M, Hartman-Filson M, Sommers M, Lewis E, Balmes JR, Moisi D, Lederman MM, Madsen KA, Woodruff PG, Hunt PW, Huang L, .

PLoS ONE 2019 ;14(10):e0223263. doi: PONE-D-19-17773. Epub.

Abstract: COPD is a common HIV comorbidity, and HIV-infected individuals have a higher incidence and earlier onset of COPD compared to HIV-uninfected individuals. While the pathogenesis of HIV-associated COPD is largely unknown, chronic inflammation may contribute. Four pneumoproteins known to be markers of lung injury and inflammation have been associated with COPD in HIV-uninfected individuals: PARC/CCL-18, SP-D, CC-16, and sRAGE. © PloS One.

HIV infection is associated with elevated biomarkers of immune activation in Ugandan adults with pneumonia.

Wang RJ, Moore J, Moisi D, Chang EG, Byanyima P, Kaswabuli S, Musisi E, Sanyu I, Sessolo A, Lalitha R, Worodria W, Davis JL, Crothers K, Lin J, Lederman MM, Hunt PW, Huang L.

PLoS ONE 2019 ;14(5):e0216680. doi: PONE-D-19-07580. Epub.

Abstract: Pneumonia is an important cause of morbidity and mortality in persons living with human immunodeficiency virus (HIV) infection. How immune activation differs among HIV-infected and HIV-uninfected adults with pneumonia is unknown. © PloS One.